Evolve is a specialist pharmaceutical and biotechnology IP firm. Our team includes scientific experts in macrophage and innate immune biology, cell therapy engineering and manufacturing, and in vivo delivery. Rose Hughes, our Patent Director, has a PhD in macrophage immunology from UCL, where she studied the innate immune responses of macrophages to viral infection.
Related technologies: CAR-T | In vivo CAR-T | Regenerative cell therapies | Lipid nanoparticles
Macrophages, literally the “big eaters” of the immune system, are critical orchestrators of the immune response. Their central role in both cancer immunity and autoimmune disease makes them an ideal candidate for cell therapy. The field is still young compared to CAR-T, and macrophages bring unique manufacturing and engineering challenges. That also means considerable opportunity for pioneering innovators to capture valuable IP.
Unlike T cells, macrophages naturally traffic into and survive within solid tumours. CAR-macrophage (CAR-M) therapy could also deliver a multi-pronged attack: direct tumour killing by phagocytosis, remodelling of the tumour microenvironment (TME) and activation of adaptive immunity, including T cells. Safety looks promising too. Early clinical trials have reported no dose-limiting toxicities, and none of the severe cytokine release syndrome (CRS) or neurotoxicity (ICANS) that often limit CAR-T.
Beyond oncology, macrophages regulate tissue repair and fibrosis, so engineered macrophages are being developed to deliver anti-fibrotic agents to scarred tissue in organs such as the liver and lungs. They may offer a safer vehicle for eliminating the pathogenic B cells behind many autoimmune disorders, and preclinical CAR-Ms targeting the SARS-CoV-2 spike protein have cleared virus without excessive inflammation.
CAR-M cells may be derived from a patient’s circulating monocytes or, for an allogeneic approach, differentiated from stem cells. The CAR is structurally similar to a CAR-T construct, with an antigen-binding domain (usually an scFv), a hinge, a transmembrane domain and intracellular signalling domains. The signalling domains, however, are adapted to macrophage biology. Domains such as FcRγ, CD3ζ, Megf10 or Toll-like receptor (TIR) domains trigger robust, antigen-dependent phagocytosis, largely through pathways such as PI3K/AKT.
The first challenge is persistence. Macrophages are highly plastic, and the immunosuppressive TME can switch anti-tumour (M1) cells into a pro-tumour (M2) state. A successful CAR-M therapy must therefore use cells engineered for phenotypic stability.
Manufacturing is the second challenge. Macrophages are hard to culture and expand ex vivo, and because they stick to the culture dish, they are difficult to harvest without damaging them. They are sensitive cells that are hard to engineer, transport and store, and they react to innate immune stimuli, including components of the viral vectors used to deliver CARs. Engineering macrophages therefore needs cell-specific protocols and real macrophage expertise.
Many strategies developed for CAR-T do not translate to macrophages, which creates a need for innovation and the potential for strong IP. Carisma Therapeutics, a leader in the field, found that its first anti-HER2 CAR-M, CT-0508, was safe in Phase 1 but showed limited efficacy. It has since shifted from differentiated macrophages to monocyte precursors, with a new lead asset, CT-0525.
As with CAR-T, there is growing interest in in vivo engineering, using mRNA-LNP delivery to create CAR-M cells inside the patient and turn a personalised, high-cost treatment into a scalable, off-the-shelf product. Carisma is working with Moderna on an in vivo platform for oncology and autoimmune disease. CREATE Medicines (formerly Myeloid Therapeutics) has two mRNA-LNP assets, MT-302 (TROP2) and MT-303 (GPC3), in Phase 1 for solid tumours including glioblastoma and hepatocellular carcinoma. Others, such as Inceptor Bio, are engineering “armoured” macrophages with better tumour infiltration and phagocytosis that can bypass the CD47/SIRPα “don’t eat me” checkpoint.
Given the manufacturing challenges, much IP has been filed on processes. Examples include Inceptor Bio’s application on making myeloid-derived cells from stem cells (WO 2025046513 A1) and Carisma’s granted US patent on treating CAR-macrophages ex vivo with a CD40 agonist (US 11739297 B2). Carisma also licenses foundational IP from the University of Pennsylvania, such as US 11498954 B2, which simply claims a modified macrophage or monocyte comprising a CAR with reduced SIRPα activity.
Product IP is generally preferred, as it is easier to enforce and harder to design around (Evolve Insights). Because CARs must be optimised for macrophages, the CAR itself can be protected. Examples are CREATE Medicines’ application on an anti-TROP2 chimeric fusion protein that dimerises with endogenous FcR-gamma, and Inceptor Bio’s WO 2024236547 A1 on a CAR with an HVEM cytoplasmic domain. The cells themselves can also be claimed, as in Resolution Therapeutics’ WO 2024068728 A1 on an engineered macrophage expressing MMP9 to treat fibrosis.
Macrophages are heterogeneous, so the definition of the product in the claims must align with the description, regulatory documents and licensing contracts. This needs particular care where the product given to patients is a monocyte precursor (Evolve Insights).
In vivo approaches offer further IP opportunities, including delivery vehicles and cell targeting (Evolve Insights), but also freedom to operate risks. An in vivo cell therapy company, Capstan (AbbVie), has already been drawn into the LNP litigation. As products reach the clinic, there will also be opportunities for clinical IP on doses, formulations, patient subpopulations, delivery methods, new uses and combination therapies.
CAR-M therapy is a bold new frontier, harnessing the innate immune system to offer better safety and a multi-faceted attack on disease, particularly in solid tumours where other cell therapies have faltered. Realising that promise needs innovative solutions to the challenges of engineering, manufacturing and persistence. That wave of innovation creates room for a valuable and defensible IP position, distinct from the crowded CAR-T field. Building it requires a deep understanding of both the science and the competitive landscape.
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